Treatment for Migraine

ABSTRACT

The present invention relates to methods for the treatment of migraine headache, cluster headache, tension type headache, trigeminal neuralgia (trigeminal headache) and headache disorders. The methods comprise administration of specific cardiac glycosides: Thevetin A and or Thevetin B to a subject in need thereof a pharmaceutically suitable preparation, in the form of nasal spray and or other modes and methods that will ensure adequate intranasal dosage, a pharmaceutically suitable preparation of the said cardiac glycosides that is sufficient to have the most desirable therapeutic effect when used as a prophylaxis, as a treatment and ameliorating agent of migraine headache and others headache disorders.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a Continuation in Part of U.S. patent application Ser. No. 13/590,134 Filled on Aug. 20, 2012

Citations (Patents)

U.S. patent application Ser. No. 12/298254 Publication Number US20090318374 A1

Also published as:

EP2013626A2, U.S. Pat. No. 8,163,270, US20120270816, WO2007127237A2, WO2007127237A3

(Sayani A P and Chien Y W (1996) Critical Reviews in Therapeutic Drug Carrier Systems, 12:85-184

Global Year Against HEADACHE October 2011-October 2012

Sciencedaily May 21, 2014

(wvvw.sciencedaily.com/releases/2014/05/140521133603.htm)

PROTA 11 (1)—Bothalia 7: 448

TECHNICAL FIELD

The present invention relates generally to methods and compositions for the treatment of migraine headaches, trigeminal neuralgia, headaches, and headache disorders. More specifically, the present invention relates to methods of treating migraine headaches, trigeminal neuralgia, headaches and head pain disorders by administering a pharmaceutically suitable composition made with and or containing Thevetin A and or Thevetin B in the form of a nasal spray, or other mode of packaging and administered intranasally. In particular, the present invention relates to methods for the treatment and or prophylaxis of migraine headache (migraine), cluster headache, tension type headaches, headache disorders, head pain or trigeminal neuralgia, by administration of Thevetin A and or Thevetin B or a pharmaceutical composition comprising Thevetin A and or Thevetin B to individuals in need of treatment thereof.

BACKGROUND OF THE INVENTION Headaches

There are severally types of headaches, however, headaches are generally classified either as primary headache or secondary headache.

Primary headaches are benign recurrent headaches that are not caused by any underlying disease or injury. Secondary headaches are caused by bacteria infection, head injury or even malignant or benign tumors.

There are many primary headaches, examples of some common primary headaches are Migraine headache, Tension type head, Cluster headache, Daily Recuring headache, Trigeminal neuralgia, Hemicrania continua. Hypnic headache, Primary Exertional headache, Primary Stabbing headache, Vascular headache, and Primary Coughing headache.

The following is basic description of a few primary headaches:

Cluster Headache

Cluster headache is a recurrent severe primary headache that is felt around one part of the head, typically around the one eye. Cluster headache attacks often occur periodically (around the same time period or season each year). In about of the clinical cases involving Cluster headache the bouts of pain last for about 4 to 12 weeks during each episode. The reason for this seasonal pattern of Cluster headache is yet not known.

BACKGROUND OF THE INVENTION Hypnic Headache

Hypnic headache is a primary headache that occurs exclusively at night, typically between 11 pm-3 am. The pain experienced during an episode of Hypnic headache can be unilateral or bilateral. The pain begins abruptly and can last between 30 minutes to 6 hours, and it is more common among women than men.

Tension Headache

A Tension headache is a primary type headache that is mild to moderate in type of headache. Tension headache (tension-type headache) is described as having the feeling of a tight band around the head or the feeling of having one head squeezed in a vise. Globally Tension headaches affect about 1.4 billion people (20.9% of the population respectively. Though tension type headache is one of the most common headaches, the epidemiology of tension headache is still not yet fiilly understood.

BACKGROUND OF THE INVENTION Headaches

The following is basic description of a few primary headaches:

Primary Exertional Headache

Primary Exertional headache is a headache that is brought about by exercise or physical exertion. It is experienced by approximately by 10% of the general population and it is more common in men than women. Primary exertional headache is likely to occur in high altitude or in a hot weather. Also when alcohol or caffeine is consumed prior to exercising primary exertional headache can be triggered. During an episode of primary exertional headache the sufferer can experience extreme sensitivity to light (photophobia), noise (phonophobia), nausea and vomiting.

Hemicrania Continua

Hemicrania continua is a rare type of unilateral primary headache that is severe and persistent and can last 3 months or even more. Hemicrania continua symptoms can mimic some aspects of migraine headache, however, Hemicrania continua clinical presentations includes daily continues headache without pain free-periods, ptosis of the eyelid, rhinorrhea (running nose), and nasal congestion. Patients that have episodes of Hemicrania continua describe the pain as stabbing, sharp, and jolting pain that is intense and unremitting pain. The cause of Hemicrania continua is unknown.

BACKGROUND OF THE INVENTION Headaches

Trigeminal Neuralgia: Trigeminal neuralgia, also known as prosopalgia or Fothergill's disease is a neuropathic disorder, characterized by episodes of intense pain in the face and head. It has been described as among the most painful conditions known. Though the pain from trigeminal neuralgia originates from the trigeminal nerve, which is the 5^(th) cranial nerve, the perception of pain felt from an episode of trigeminal neuralgia can originate from the eye, ear, nose, lips, forehead_(;) scalp, mouth, jaw or side of the face. Trigeminal neuralgia is often mistaken for migraine headache.

BACKGROUND OF THE INVENTION Migraine Headache

Though the epidemiology of migraine headache and headache disorders continues to evolve as the medical sciences related to treating and diagnostics of migraine and other headache disorders continue to improve, however, migraine headache is generally understand to be a severe, painful and disabling headache often affect one half of the head (hemi-crania), that can be preceded or accompanied by sensory warning signs such as flashes of light, blind spots, tingling in the arms and legs, nausea, vomiting, and heightened sensitivity to light and sound. The excruciating pain that migraines bring can last for hours or even days.According to the United Nations' World Health Organization, headache disorders are a public-health concern given the large amount of associated disability and financial costs to society. As headache disorders are most troublesome in the productive years (late teens to 50s), estimates of their financial cost to society—principally from lost working hours and reduced productivity—are massive. In the United Kingdom, for example, some 25 million working- or school-days are lost every year because of migraine headache. Globally it is estimated that about 303 million people, including 43 million Europeans and between 24 million to 37 million Americans suffers from migraine headache. According to the Global Year Against HEADACHE October 2011-October 2012, “headaches are the prevalent neurological disorders and among the most frequent symptom seeing in general practice. Tension type headache is more common than migraine. The prevalence of migraine in children and adolescents is 7.7%. There is sexual dimorphism between male and female for migraine headache patients is 2-3 females to 1 male remains stable across countries”.

BACKGROUND OF THE INVENTION Migraine headache

(1)

According to the current International Headache Society's classification system., there are seven types of migraine, including Migraine with Aura, Migraine without Aura, Migraine without headache, Familial Hemiplegic Migraine, Migraine with Brainstem Aura, Retinal Migraine, and Chronic Migraine.

The three major types of migraine headaches are:

Migraine without Aura, (formerly called Common Migraine), is the most frequent type of migraine. Symptoms include moderate to severe pulsating headache pain that occurs without warning and is usually felt on one side of the head, along with nausea, confusion, blurred vision, mood changes, fatigue, and increased sensitivity to light, sound, or smells. Attacks typically last 4-72 hours, and repeat a few times a year to a few times a week (see Chronic Migraine, below). Movement generally makes the attack worse. Importantly, this Migraine without Aura is the type most prone to worsen with frequent use of symptomatic medication.

Migraine With Aura, (formerly called Classic or Complicated Migraine), includes visual disturbances and other neurological symptoms that appear about 10 to 60 minutes before the actual headache and usually last no more than an hour. You may temporarily lose part or all of your vision. The aura may occur without headache pain, which can strike at any time. Less frequent aura symptoms include an abnormal sensation, numbness, or muscle weakness on one side of the body; a tingling sensation in the hands or face; trouble speaking; and confusion. Nausea, loss of appetite, and increased sensitivity to light, sound, or noise may precede the headache. Migraine aura can also occur without a headache.

BACKGROUND OF THE INVENTION Migraine Headache

(2)

Migraine with Brainstem Aura, (formerly called Basilar-Type Migraine), mainly affecting children and adolescents, this includes Migraine with aura symptoms that originate from the brainstem, but without motor weakness. It occurs most often in teenage girls and may be associated with their menstrual cycle. Symptoms include partial or total loss of vision or diplopia, dizziness and vertigo, poor muscle coordination, slurred speech, tinnitus, and syncope. Many factors can trigger migraine headache attacks, including alteration of sleep-wake cycle; missing or delaying a meal; medications that cause a swelling of the blood vessels; daily or near daily use of medications designed for relieving headache attacks; bright lights, excessive exposure to sunlight, video games, TV and movie viewing; certain foods; and excessive noise. Stress and or underlying depression are also known trigger factors of migraine headache.

BACKGROUND OF INVENTION Current Treatments (Migraine)

(1)

There are many treatment regimes utilized for migraine headache and symptoms associated with migraine (example nausea), from Preventive treatment (prophylaxis type of treatment that tries to stop the migraine headache from occurring), Acute treatment (treating the migraine headache as soon as they occur) and Rescue treatment (dealing with the migraine headache attack, if the acute treatment does nut work), although it is important to note that Triptans are a family of tryptamine-based drugs including but not limited to Sumatriptan, Rizatriptan, Naratriptan, Zolmitripan, Eletripan, Almotripan, Frovatripan, Avitripan and Donitripan, does enjoys a limited measure of success as a treatment option that is used as an abortive medication to treat migraine headache, however, to date there is no single treatment strategy (including prophylaxis) that successfully alleviates migraine in majority of the patients that have migraine headache. And it is important to note that Triptans are not considered as a cure for migraine headache. Some NSAID (Non-Steroidal Anti Inflammatory Drugs), Acetominophen, Acetyl Salicyclic Acid (Aspirin) or Aspirin in combination with caffeine (example “Excedrin Migraine”) have all been marketed and utilized as migraine headache treatment, however, in most cases they offer very limited measure of success when employed against migraine and to this date it is generally accepted that there is no cure or treatment for migraine headache that will give migraine sufferers sustained relief from migraine headache to the point whereby they may feel cure or be able to go about their daily activities without being disabled by the migraine headache during a migraine attack.

BACKGROUND OF INVENTION Current Treatments (Migraine)

(2)

One of the treatment options for treating migraine headache is migraine surgery. The surgical procedure is often undertaken with the aim of reducing or as a prophylaxis for migraine headache, however, because no accurate estimate exist about the efficacy of migraine surgery as an effective treatment of migraine headache, it is not considered a cure or an effective treatment for migraine headache, especially given the inherently high risks associated with the surgery. It is clear that to date there is no treatment for migraine headaches, cluster headaches and tension type headaches that can offer effective treatment and or relief to the point that the migraine headache, cluster headache or tension type headache is no longer considered by the patient to be a disability, or cure from these disabling conditions.

BACKGROUND OF INVENTION Current Treatments (Cluster Headache)

Currently there is no cure for cluster headaches. The goal of any treatment headache is to decrease the severity of the pain and shorten the duration of the headache and as a prophylaxis that may prevent onset of a cluster headache attack. There are acute treatments that are used to give some relief from cluster headache pains, and while they are not considered a cure, these acute treatments include but not limited to Oxygen; when 100% oxygen is administered through a mask to a person having an episode of cluster headache attack offers some relief, however, although there are portable oxygen cylinders currently available, many consider carrying an oxygen cylinder and the regulator that comes with its as impractical to use or carry with them. Injectable form of sumatripan (Imitrex), which is currently used against some forms of migraine headache has been as treatment for cluster headache, however, it takes time for its impact to be notice by the patient and because it is administered intravenously at a physician office, the added inconvenience of going to a clinical settings for a treatment makes some patients reluctant to engage in a treatment regime that requires so many steps. Additionally, though the treatment itself may give some temporal relief from cluster headache it is not considered a cure.

Current Treatments (Tension Headache)

Currently several OTC (Over the Counter) pain medications such as Aspirin, Ibuprofen (Non-Steroidal Anti Inflammatory Drugs) and prescription medications, including but not limited to naproxen, indomethacin and as well as Triptans and narcotics including opiates are used to treat Tension headaches, and while they offer some form of relive, for example some of the narcotics used to treat Tension headaches such as opiates can be habit forming.

Also NSAIDs (Non-steroidal Drugs) including those used to treat tension type headache, such as for example, Indomethacin, can increase cardiovascular thrombotic events, including increased risk for myocardial infarctions and stroke.

BACKGROUND OF INVENTION Current Treatments (Hemicrania Continua)

Hemicrania continua headache responds favourably to Indomethacin (Indomethacin is non-steroidal inflammatory drug) and other NSAID drugs, however, Indomethacin and the other pharmaceutical drugs when used to treat Hemicrania continua must administered on daily basis for long periods of time, and by administering those drugs to the patient for a long period increases the potential for cardiovascular thrombotic events, Including increased risk for myocardial infarctions and stroke in the patient, making it undesirable.

Current Treatments (Trigeminal Neuralgia)

There are variety of treatment options for treating trigeminal neuralgia that may help reduce the rate of occurrence and the intensity of the pain, from using over the counter pain killers, prescription grade pain killers, anti-epileptic drugs, “Carbamazepine”, to surgery, however, typical pain killers cannot effectively treat trigeminal neuralgia, and anti-epileptic drugs many known have undesirable side effects and surgery has inherent dangers that may make that treatment option unsuitable. There is no effective drug to this day that can cure trigeminal neuralgia.

BRIEF SUMMARY OF THE INVENTION

Provided herein are methods for preventing and treating migraine headache, tension type headache, trigeminal neuralgia, cluster headache, hemicrania continua, tension type headache and other primary type headaches comprising of administering a intranasally, a pharmaceutically suitable composition containing Thevetin A and or Thevetin B. Some aspects of the invention include methods whereby the said composition is administered as a nasal spray with or without excipients. Some aspects of the invention include methods whereby the said composition is delivered as a nasal spray powder with or without the aid of a propellant. Some aspects of the invention include methods whereby the headache is a primary headache or secondary headache. Some aspect of the invention includes methods of treating migraine associated headaches. Some aspects of the invention include methods of delivering the said composition via a nebulizer. Some aspects of the invention include excipients that allow uniform delivery of the treatment to patients in need of treatment thereof. Some aspects of the invention include adding excipients to the compound that will mask the taste thereby making it more convenient for patients to use.

DETAILED DESCRIPTION OF THE INVENTION (Definitions)

As used herein, and unless otherwise specified, the term “treatment” or “treating pain” regards to administration to an individual in need of treatment an agent of interest wherein the said agent alleviates or prevents a pathology for which the individual is being treated. “Treatment for headache pain”, “treatment of headache”, “treatment of head pain”, “treatment of migraine”, or treatment of migraine headache” refers to the treatment of migraine and associated headache disorders. Treatment for headache pain”, “treatment of headache”, “treatment of head pain”, or “trigeminal neuralgia”, refers to the treatment of trigeminal neuralgia and associated headache disorders.As used herein, and unless otherwise specified, the term “prevention”, “prophylaxis” or “pain preventing” refers to administration to an individual of an agent of interest wherein the agent alleviates or prevents a pathology for which the individual is being treated. As used herein, “Thevetin A” and or “Thevetin B” are cardiac glycosides having biological activity that can be natural occurring and can also be man-made synthetic, its analogues or derivatives thereof. As used herein “migraine” includes migraine headache, migraine without aura, migraine with aura, and migraine with aura but without headache. As used herein, “surfactant” and “surfactants” refers to a substance that is utilized to reduce surface tension, and or used to increase the emulsification of two separate and distinct mediums, example, is emulsification of water and a lip substance such as oil.

DETAILED DESCRIPTION OF THE INVENTION Active Compounds

Cardiac glycosides are bioactive drug compounds, and the specific cardiac glycosides Thevetin A and or Thevetin B are drug compounds. Thevetin A and Thevetin B are often extracted together with other cardiac glycosides, namely, Peruvoside, Thevofolin, Oleandrin, Neriifolin and Thevetoxin from the White Oleander plant (Thevetia Peruviana) or the White Oleander plant (Nerium Oleander). Apart from the white oleander and the yellow oleander plants, there are other natural sources for Thevetin A and Thevetin B, including plant and animal sources, also Thevetin A and Thevetin B analogues, and synthetic man-made. Pure form of Thevetin A and Thevetin B are commercially available. Thevetin A is also known as Cannogenin 3-O-gentiobiosylthevetoside and Thevetin B is also known as Cerebroside.

DETAILED DESCRIPTION OF THE INVENTION Excepients

An excipient or excipients are natural or synthetic substances added alongside active ingredient of pharmaceutical drugs. The intended purpose of adding excipients to drugs is to act as diluents that dilutes and controls potency of the drug, preservatives that increase shelf life by retarding spoilage, acidulants and or alkalizing agents that adjust the pH to a more desirable level, flavours that improve taste, aftertaste and aroma, anti-oxidants that retards oxidation and increase shelf life, surfactants that increase the bioavailability of the active ingredient by reducing surface tension, bulking agent that helps control the bioavailability of the active drug compound and polymers that may help control the viscosity of the drug and improve uniform distribution of the drug, example when the drug contains ingredients with different level of solubility in the diluent, and glycols may also be added to prevent the dry-out of the drug and improve the overall comfort of the patient as well as improve the “plasticity” of the drug. Some excipients also improve the overall performance of the drug that they are included in. Example pharmaceutical grade of the surfactant Polysorbate-20 and its analogues are sometimes added to nasal spray to increase the “spray pattern” and “plume geometry” of the nasal spray, thereby improving it efficiency.

DETAILED DESCRIPTION OF THE INVENTION Art of Enablement, Sample Formulating and Sample Compounding

The fulluwing are examples of basic formulating and compounding examples for reference purposes only.

Nasal Spray (Suspension)

This invention relates to methods of treating migraine headaches and headache disorders by administering intranasally a pharmaceutically suitable preparation containing specific cardiac glycosides: Thevetin A and or Thevetin B intranasally in a form of a “Nasal Spray Suspension” to a patient in need of a treatment thereof.

Pharmaceutical suitable grades of:

Distilled Water (Diluent): 80%-99%

Sodium Carboxyl Methyl Cellulose (polymer and suspending agent): (q.s)

Microcrystalline Cellulose (polymer and suspending agent): (q.s)

Polysorbate-80 (surfactant and a spreading agent): quantum satis (q.s)

Sodium Benzoate or Benzalkonium Chloride (preservative agents): quantum satis (q.s)

Tocophyrol Acetate (Vit.E) (anti-oxidant): quantum satis (q.s)

EDTA (chelating agent): quantum satis (q.s)

Pharmaceutical Grade Thevetin A and or Thevetin B (active): quantum satis (q.s)

DETAILED DESCRIPTION OF THE INVENTION

The distilled water be weighted into a cleaned stainless steel vessel, and agitated until a vortex is formed, then the polymers (Sodium Carboxyl Methyl Cellulose and or Microcrystalline Cellulose) is weighed and slowly sprinkled into the vortex and mixed until a clear and a clean suspension mucilage without particulates is formed. The suspension is slowly heated to about 60 o C and the other ingredients are added, agitated and heated to 80 o C for about 30 minutes. The suspension is slowly cooled to room temperature of about 21 o C, the suspension is then filtered and packaged into suitable packaged, example, nasal sprayers.

PS: “Quantum satis” or q.s. means “quantity sufficient but not exceeding”.

DETAILED DESCRIPTION OF THE INVENTION Art of Enablement, Sample Formulating and Sample Compounding

The fulluwiitg are examples of basic formulating and compounding examples for reference purposes only.

Nasal Spray (“Dry Powder”):

This invention relates to methods of treating migraine headaches and headache disorders by administering intranasally a pharmaceutically suitable preparation containing specific cardiac glycosides: Thevetin A and or Thevetin B intranasally in a form of a “Nasal Spray Dry Powder” to a patient in need of treatment thereof.

Pharmaceutical suitable grades of

Oleic Acid (bulking agent): q.s

Dextrose (bulking agent): q.s

Polysorbate 80 (surfactant): q.s.

Thevetin A and or Thevetin q.s

“Propellant” (Tetrafluoroethane): q.s.

The ingredients are weighted and added blended in a “powder mixer” such as “guttered mixer” then the “batch” is transferred to a stainless steel jet mill or other suitable implement, where it is milled and micronized until a suitable particle size and uniformity is obtained. Example of a good particle size for this particular instance would be 6 microns. After the desirable particle size is obtained, the admixture is then packaged into a pressurized metered-dose aerosol units or non-pressurized metered dose units.

PS: “Quantum satis” or q.s. means “quantity sufficient but not exceeding”.

DETAILED DESCRIPTION OF THE INVENTION (Art of Enablement, Sample Formulating and Sample Compounding)

The following are examples of basic formulating and compounding examples for reference purposes only.

Nebulizer (Suspension)

This invention relates to methods of treating migraine headaches and headache disorders by administering intranasally a pharmaceutically suitable preparation containing specific cardiac glycosides: Thevetin A and or Thevetin B intranasally via a “nebulizer” to a patient in need of treatment thereof.

Pharmaceutical suitable grades of

Distilled Water (Diluent): 80%-99% (or q.s)

Sodium Carboxyl Methyl Cellulose (polymer and suspending agent): (q.s)

Microcrystalline Cellulose (polymer and suspending agent): (q.s)

Polysorbate-80 (surfactant and a spreading agent): quantum satis (q.s)

Sodium Benzoate or Benzalkonium Chloride (preservative agents): quantum satis (q.s)

Tocophyrol Acetate (Vit.E) (anti-oxidant): quantum satis (q.s)

Flavoring Agent (Intransal suitable): (q.s)

Pharmaceutical Grade Thevetin A and or Thevetin B (active): quantum satis (q.s)

DETAILED DESCRIPTION OF THE INVENTION Example Compounding Method (For Reference Purpose Only)

The distilled water be weighted into a cleaned stainless steel vessel, and agitated with example an impeller mixer, until a vortex is formed, then the polymers (Sodium Carboxyl Methyl Cellulose and or Microcrystalline Cellulose) is weighed and slowly sprinkled into the vortex and mixed until a clear and a clean suspension mucilage without particulates is formed. The suspension is slowly heated to about 60 o C and the other ingredients are added, agitated and heated to 80 o C for about 30 minutes. The suspension is slowly cooled to room temperature of about 21 o C, the suspension is then filtered and packaged into Nebulizer or a suitable container and decanted into a nebulizer for use by a patient who due an illness or injury may not be able to a nasal spray or may not wish to use a nasal spray.

PS: “Quantum satis” or q.s. means “quantity sufficient but not exceeding”.

DETAILED DESCRIPTION OF THE INVENTION (Art of Enablement, Sample Formulating and Sample Compounding)

The following arc examples of basic formulating and compounding examples for reference purposes only.

Nasal Spray (Emulsion)

This invention relates to methods of treating migraine headaches and headache disorders by administering intranasally a pharmaceutically suitable preparation containing specific cardiac glycosides: Thevetin A and or Thevetin B intranasally in a form of a “Nasal Spray Suspension” to a patient in need of treatment thereof.

Pharmaceutical suitable grades of:

Distilled Water (diluent): 80%-99%

Sodium Carboxyl Methyl Cellulose (polymer and suspending agent): (q.s)

Polysorbate-80 (surfactant and a spreading agent): quantum satis (q.s)

Glycerol Monostearate (CMS): quantum satis (q.s)

Mineral Oil (Parafin Oil): quantum satis (q.s)

Sodium Benzoate or Benzalkonium Cbloride (preservative agents): quantum satis (q.s)

Tocophyrol Acetate (Vit.E) (anti-oxidant): quantum satis (q.s)

EDTA (chelating agent): quantum satis (q.s)

Pharmaceutical Grade Thevetin A and or Thevetin B (active): quantum satis (q.s)

DETAILED DESCRIPTION OF THE INVENTION

The distilled water be weighted into a cleaned stainless steel vessel, and agitated until a vortex is formed, then the polymers (Sodium Carboxyl Methyl Cellulose and or Microcrystalline Cellulose) is weighed and slowly sprinkled into the vortex and mixed until a clear and a clean suspension mucilage without particulates is formed. The water phase: the water and the C.M.0 and etc and the oil phase (the light mineral oil, the polysorbate-80 and the G.M.S) are heated separately until about 80o C, then one phase, example, the oil phase is added to the water phase, and agitated rapidly with an impeller mixer or other suitable mixer until an “emulsion” is formed. The emulsion is cooled to about 25 o C and packaged in Nasal Spray, using piston fillers or other packaging machines.

PS: “Quantum satis” or q.s. means “quantity sufficient but not exceeding”.

DETAILED DESCRIPTION OF THE INVENTION Routes of Administration

This invention relates to methods of treating migraine headaches and related headaches, by administering to a patient in need of treatment thereof a pharmaceutically suitable preparation, containing specific cardiac glycosides: Thevetin A and or Thevetin B. The primary route of administering this invention is to use it as a nasal spray, either in a suspension “solution”, suspension “emulsion” or “metered—dose dry powder method” which is also known as Dry Powder Inhaler or DPI, which is increasingly becoming more common as means of delivering active pharmaceutical drugs intranasally. However, should the patient be incapacitated or unwilling to use the drug intranasally as a nasal spray, a “special device” or delivered method, example, a “specifically designed or specifically calibrated” nebulizer can be prescribe by a physician to be employed in delivering the said invention to a patient in of treatment thereof. According to (Sayani AP and Chien Y W (1996) Critical Reviews in Theraputic Drug Carrier Systems, 12:85-184—“Intranasal delivery has a number of advantageous features including comparatively high bioavailability, rapid kinetic of absorption and avoidance of a first-pass effect in the liver”. In order to avoid hepatic first-pass metabolism, intranasal delivery of the treatment method described in this invention is ideal.

DETAILED DESCRIPTION OF THE INVENTION Dosage

The dosage of the invention, which relates to methods of treating migraine headaches and headache disorders by administering intranasally a pharmaceutically suitable preparation, containing the specific cardiac glycosides: Thevetin A and or Thevetin B, would depend on the age, weight, the overall health of the patient being treated and physician treating the patient, based on critical factors would determine how best to prescribe the said preparation. However, for example, an effective dose of about 1 mcg to 85 mcg of the active compound of Thevetin A and or Thevetin B in a 50 ml total volume of the said preparation when used by an adult of about 75 kg weight, is usually sufficient, when used twice or thrice daily as a nasal spray or when used nasally twice or thrice daily is very effective treatment for primary headaches, including migraine headache, trigeminal headache, cluster headache, tension type headache, hypnic headache. It is important to note that a regulatory body, the physician who prescribe the drug, and the legal constraints is what will ultimately establish the dosage level. Intranasally in this context means nasal spray or nasal drop, or other methods that will allow the said drug to be safely and effectively dosed via or through the nasal cavity. In another embodiment of the invention, between the percentage rate of 0.001 to 22% of Thevetin A and or Thevetin B in a pharmaceutically effective preparation administered intranasally and or in the form of nasal spray is sufficient to ameliorate, treat and a prophylaxis against migraine headaches and other primary headaches.

DETAILED DESCRIPTION OF THE INVENTION Derivative of an Active Ingredient

In chemistry a derivative is a compound that is derived from similar compound by some chemical or a physical process.

Example, according to Uber-Bucek E, Harron M, Pham Huy C, and Dadoun H (Laboratorie de Pharmacognosie, Faculty des Sciences, Chatenay Malabry, France) in the Journal of Pharmaceutical and Biomedical Analysis (1992, 10 (6): 413-419): “The cardiac glycoside Thevetin B genin is structurally identical to digitoxigenin”. Another example of a chemical analogue is the comparison of the synthetic chemical compound “vanillin” and the natural vanillin. “Vanillin” which is synthetic may be produced as a by-product of wood alcohol or produced by using petrochemicals or as a by-product from the paper industry, is identical to the vanillin in vanilla beans, however, it is not obtained from the vanilla beans.

PRIOR ART

There have been several published literature and patents disclosures that list methods of treating some forms of primary headaches using plants extracts that contains various levels of one or more cardiac glycosides and as expected other bioactive compounds. There are also numerous published literatures that teach the administration of drugs intranasally to treat headaches, neurological disorders and other brain diseases. Example is an article that was published by ScienceDaily, “Breakthroug: Nasal spray may soon replace pills for delivering drugs to the brain” ScienceDaily, 21 May, 2014. This particular article cites a study by Massimilano Di Cagno, assistant professor of Department of Physics, Chemistry and Pharmacy at the University of Southern Denmark, who in the article cited above, allegedly advocate the treatment of certain brain diseases by administering drugs intranasally. In the article Massimilano Di Cagno allegedly stated in that “People with brain diseases are often given huge amounts of unnecessary drugs. During a long life, or if you have a chronic disease, this may become problematic to your health”. Massimilano Di Cagno and his colleagues are said to have tested a natural sugar and they reported said that this particular polymer is not only capable of carrying drugs through the nasal wall but also most importantly—releasing the drug where it is needed. “This is an important breakthrough, which will bring us closer to delivering brain drugs by nasal spray” Missimilano Di Cagno, added to his statement. The implication being that pharmaceutical drugs that are used to trait brain related disorders can be administered intranasally or as a nasal spray.

PRIOR ART

The medicinal use of plants extracts that contains various cardiac glycosides are in published literature. Example, the esteemed journal Bothalia which has been in publication since 1921, and is now published as “The African Biodiversity & Conservation”,teaches in PROTA 11 (1)—Bothalia 7: 448, that the plant Acokanthera oppositifolia (also known as “Bushman poison” in English and “Msungu” in Swahili) which contains cardiac glycosides “In South Africa root powder or leaf powder is sniffed to cure headache, while leaf infusion is used as a nasal spray for the same purpose”. Another example of the use of cardiac glycosides as a treatment is the United Patent US-2009/0318374 A1, Harrington (Michael G. Harrington) et al cites the use of various cardiac glycosides intranasally as a method for treating headache, without specifically mentioning Thevetin A and Thevetin B; and we also know that as of date, there is no cure for migraine headache, this makes this distinct invention worthy. No literature or patent(s), both published and or cited herein specifically mentions the use of Thevetin A and or Thevetin B, when used, example, in a pharmaceutically suitable preparation, and used intranasally (eg., a nasal spray) can be used as a treatment for migraine headache or other headaches. 

1. A method for treating a migraine headache, comprising of administering to a subject in need thereof, an effective dose of a pharmaceutically suitable preparation, containing one or more of the following selected group of specific cardiac glycosides: Thevetin A and or Thevetin B.
 2. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache, was administered intranasally.
 3. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache was administered as a nasal spray.
 4. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache, contained excipients.
 5. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache, did not contain any excipients.
 6. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache, contained the cardiac glycoside Thevetin A.
 7. The method according to claim 1, wherein the said pharmaceutical suitable preparation for treating migraine headache, contained the cardiac glycoside Thevetin B.
 8. A method for treating a headache, comprising of administering to a subject in need thereof, an effective dose of a pharmaceutically suitable preparation, containing one or more of the following selected group of specific cardiac glycosides: Thevetin A and or Thevetin B.
 9. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating headache, was administered intranasally.
 10. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating heartache was administered as a nasal spray.
 11. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating headache, contained excipients.
 12. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating headache, did not contain any excipients.
 13. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating headache, contained the cardiac glycoside Thevetin A.
 14. The method according to claim 8, wherein the said pharmaceutical suitable preparation for treating headache, contained the cardiac glycoside Thevetin B.
 15. A method for treating a primary headache, comprising of administering to a subject in need thereof, an effective dose of a pharmaceutically suitable preparation, containing one or more of the following selected specific group of cardiac glycosides: Thevetin A and or Thevetin B.
 16. The method according to claim 15, wherein the said pharmaceutical suitable preparation for treating headache, was administered intranasally.
 17. The method according to claim 15, wherein the said pharmaceutical suitable preparation for treating headache was administered as a nasal spray.
 18. The method according to claim 15, wherein the primary headache being treated is a tension type headache.
 19. The method according to claim 15, wherein the primary headache being treated is a tension type headache.
 20. The method according to claim 15, wherein the primary headache being treated is a cluster headache. 